As used herein, the term "erectile dysfunction" refers to certain disorders of the cavernous tissue of the penis and the associated facia which produce impotence, the inability to attain a sexually functional erection; priapism, the persistent and often painful erection of the penis; and Peyronie's syndrome, a condition characterized by fibrosis of the cavernous tissue and associated painful and distorted erection of the penis. Erectile dysfunctions, particularly impotence, affect a substantial number of patients. For example, impotence is estimated to affect approximately 10 million American men and can result from any of numerous physiological or psychological factors which cause the blood flow to and from the penis to remain in balance thereby preventing retention of sufficient blood to cause rigid dilation of the corpus cavernosa and spongiosa. As used herein, the term "impotence" is used in its broadest sense as the inability to attain a sexually functional erection when desired.
Treatments for impotence include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and .alpha.-adrenergic blocking agents (hereafter ".alpha.-blockers"), vascular surgery, implanted penile prostheses, vacuum devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis. See Robert J. Krause, et al., Impotence, N. Eng. J. Med. Vol. 321, No. 24, Dec. 14, 1989 for a general discussion of the current state of the art.
Originally Dr. Latorre and later Dr. R. Verag of Paris demonstrated that impotence could be physiologically treated by the direct injection of a vasoactive drug into a patient's epigastric artery and thereafter thousands of patients have treated their impotence by self injection of such drugs directly into the corpora cavernosa. Forward, l.sup.er Symposium International Sur L'Erection Pharmacologigue, Nov. 17-19, 1989, Paris, p 2; R. Virag, et al, Intracavernous Injection of Papaverine as a Diagnostic and Therapeutic Method in Erectile Failure, Angiology, 35, pp 79-87, 1984; (See also, U.S. Pat. Nos. 4,127,118, 4,766,889 and 4,857,059 which are incorporated herein by reference). The drugs most commonly used include .alpha.-blockers, such as the long acting phenoxybenzamine and the short acting phentolamine, smooth muscle relaxants such as papaverine, prostaglandins having a vasoactive function such as prostaglandin-E.sub.1 (PGE.sub.1) and combinations of such drugs having different receptor effects to enhance therapy. Erection producing intracavernous injection doses of papaverine are typically in the range of about 7.5 to 160 mg, of phentolamine are in the range of about 0.1 to 10 mg of and of PGE.sub.1 are in the range of about 2.5 to 50 micrograms. See for example, Kurkle, et al, Injection Therapy for Impotence Urol. Clin. of America, Vol. 15, No. 4, November 88, pp 625-629 and N. Ishii, et al, Intra Cavernous Injection of Prostaglandin E for the Treatment of Erectile Impotence, J. of Urol., Vol. 141, February 1989, pp 323-325. Vasoactive intestinal peptides at doses of 10-100 .mu.g have also been reported as producing erection on intracavernous injection. See also, H. Handelsman, Diagnosis and Treatment of Impotence, U.S. Dept. of Health Services, Agency for Health Care Policy and Research, April 1990, for a summary of intracavernal injection and other treatment of impotence.
Although intracavernous injection of vasoactive drugs can produce a relatively rapid onset of erection in patients suffering from impotence attributable to venous leakage or arterial insufficiency; patients often find the injections psychologically disturbing, painful, traumatic or inconvenient as evidenced by a high discontinuance rate. See S. Althouf, et al, Why Do So Many People Drop Out From Auto-Injection Therapy for Impotence?, Journal of Sex & Marital Therapy, Vol. 15, No. 2, 1989, pp 121-129. Adverse side effects including priapism, corporeal nodules and diffuse fibrosis, drug tolerance, bruising and hematomas. Swelling and ulceration of penile skin at the injection site have also been reported.
Nevertheless, because of the relatively innocuous intervention involved and the high failure rate of penile prostheses, the pharmacological approach to the treatment of impotence is still quite advantageous to a large number of patients and could be even more so if the side effects could be avoided. The administration of vasodilators via the male urethra has been disclosed in Voss, U.S. Pat. No. 4,801,587 and Kock, EPA 0357581 to produce erections as has the transurethral administration of testosterone, S. M. Milco, Bulletins et Memoirs de la Societa Roumaine D'Endocrinologie, Vol. 5, pp 434-437 (December 1939), strychnine and another drug (citation to be provided). It has also been suggested that cocaine administered transurethrally could contribute to an erection although the reported side effects were catastrophic, JAMA, Vol. 259, No. 21, page 3176 (1988).
Priapism is less common than impotence and can be attributed to various causes. It has been associated with diseases producing intravascular agglutination or sludging, such as leukemia, and pharmacological priapism has been reported in a small percentage of patients who are treated for impotence by intracavernous injection. Priapism has been treated by intracavernous injection of vasoconstrictors such as .alpha.-adrenergic receptor agonists (hereafter ".alpha.-agonist"). The reported effective doses of the .alpha.-agonist, phenylephrine, are in the range of about 0.1 to 2 mg.
Peyronie's syndrome is a condition of unknown etiology characterized by fibrosis of the cavernous tissues and painful and distorted erections. The current treatment consists of injection of steroids and other anti-inflammatory agents into the site of the fibrosis.
With respect to administration of drugs directly to the penis, medicated catheters such as described in U.S. Pat. No. 4,640,912 have been used to prevent or treat localized infections and irritation of the urethra and bladder; a nitroglycerin coated, erection inducing condom is disclosed in U.S. Pat. No. 4,829,991; the transurethral administration of certain drugs is suggested in U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and 4,746,508; and medicated urethral suppositories, inserts or plugs, typically containing anti-infective agents or spermicides are disclosed in U.S. Pat. Nos. 1,897,423, 2,584,166, 2,696,209 and 3,373,746, for example. As noted above, Voss, Kock, Milco, and others disclose introducing agents into the urethra to induce erections.
According to our invention, we have provided methods and dosage forms for the treatment of erectile dysfunctions which are painless, capable of rapidly, safely and effectively producing erection of the penis in the case of impotence, detumescence of the penis in the case of priapism and administration of anti-inflammatory drugs to fibrotic sites in the case of Peyronie's syndrome without the above described adverse side effects and with a high degree of patient acceptability.